Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis

Abstract

Mutations in coding and non-coding regions of FUS cause amyotrophic lateral sclerosis (ALS). The latter mutations may exert toxicity by increasing FUS accumulation. We show here that broad expression within the nervous system of wild-type or either of two ALS-linked mutants of human FUS in mice produces progressive motor phenotypes accompanied by characteristic ALS-like pathology. FUS levels are autoregulated by a mechanism in which human FUS downregulates endogenous FUS at mRNA and protein levels. Increasing wild-type human FUS expression achieved by saturating this autoregulatory mechanism produces a rapidly progressive phenotype and dose-dependent lethality. Transcriptome analysis reveals mis-regulation of genes that are largely not observed upon FUS reduction. Likely mechanisms for FUS neurotoxicity include autophagy inhibition and defective RNA metabolism. Thus, our results reveal that overriding FUS autoregulation will trigger gain-of-function toxicity via altered autophagy-lysosome pathway and RNA metabolism function, highlighting a role for protein and RNA dyshomeostasis in FUS-mediated toxicity.

Data availability

RNA-seq data have been deposited in NCBI's Gene Expression Omnibus with the GEO series accession number GSE125125.

The following data sets were generated

Article and author information

Author details

  1. Shuo-Chien Ling

    Department of Physiology, National University of Singapore, Singapore, Singapore
    For correspondence
    shuochien@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0300-8812
  2. Somasish Ghosh Dastidar

    Neurology, Duke University, Durham, United States
    Competing interests
    No competing interests declared.
  3. Seiya Tokunaga

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  4. Wan Yun Ho

    Department of Physiology, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  5. Kenneth Lim

    Department of Physiology, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  6. Hristelina Ilieva

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Philippe A Parone

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. Sheue-Houy Tyan

    Department of Medicine, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  9. Tsemay M Tse

    Department of Physiology, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  10. Jer-Cherng Chang

    Department of Physiology, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  11. Oleksandr Platoshyn

    Department of Anesthesiology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  12. Ngoc B Bui

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  13. Anh Bui

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  14. Anne Vetto

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  15. Shuying Sun

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  16. Melissa McAlonis-Downes

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  17. Joo Seok Han

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  18. Debbie Swing

    Mouse Cancer Genetics Program, National Cancer Institute, Frederick, United States
    Competing interests
    No competing interests declared.
  19. Katannya Kapeli

    Department of Physiology, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  20. Gene W Yeo

    Department of Cellular and Molecular Medicine, Stem Cell Program, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  21. Lino Tessarollo

    Mouse Cancer Genetics Program, National Cancer Institute, Frederick, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6420-772X
  22. Martin Marsala

    Department of Anesthesiology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  23. Christopher E Shaw

    Institute of Psychiatry, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  24. Greg Tucker-Kellogg

    Department of Biological Sciences, National University of Singapore, Singapore, Singapore
    Competing interests
    No competing interests declared.
  25. Albert R La Spada

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6151-2964
  26. Clotilde Lagier-Tourenne

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  27. Sandrine Da Cruz

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  28. Don W Cleveland

    Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, United States
    For correspondence
    dcleveland@ucsd.edu
    Competing interests
    Don W Cleveland, Reviewing editor, eLife.

Funding

National Medical Research Council (NMRC/OFIRG/0001/2016)

  • Shuo-Chien Ling

Ministry of Education - Singapore (MOE2016-T2-1-024)

  • Shuo-Chien Ling

National Institutes of Health (R01 AG033082)

  • Albert R La Spada

Wellcome

  • Christopher E Shaw

National Institutes of Health (R01 NS041648)

  • Albert R La Spada

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All studies were carried out under protocols approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (UCSD) and the National University of Singapore (NUS), and were in compliance with Association for Assessment of Laboratory Animal Care guidelines for animal use. All studies were performed in such a manner as to minimize group size and animal suffering. The approved NUS protocol numbers are BR17-0928 and R16-0954.

Reviewing Editor

  1. J Paul Taylor, St Jude Children's Research Hospital, United States

Publication history

  1. Received: August 5, 2018
  2. Accepted: February 11, 2019
  3. Accepted Manuscript published: February 12, 2019 (version 1)
  4. Version of Record published: February 25, 2019 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Shuo-Chien Ling
  2. Somasish Ghosh Dastidar
  3. Seiya Tokunaga
  4. Wan Yun Ho
  5. Kenneth Lim
  6. Hristelina Ilieva
  7. Philippe A Parone
  8. Sheue-Houy Tyan
  9. Tsemay M Tse
  10. Jer-Cherng Chang
  11. Oleksandr Platoshyn
  12. Ngoc B Bui
  13. Anh Bui
  14. Anne Vetto
  15. Shuying Sun
  16. Melissa McAlonis-Downes
  17. Joo Seok Han
  18. Debbie Swing
  19. Katannya Kapeli
  20. Gene W Yeo
  21. Lino Tessarollo
  22. Martin Marsala
  23. Christopher E Shaw
  24. Greg Tucker-Kellogg
  25. Albert R La Spada
  26. Clotilde Lagier-Tourenne
  27. Sandrine Da Cruz
  28. Don W Cleveland
(2019)
Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis
eLife 8:e40811.
https://doi.org/10.7554/eLife.40811

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